BACKGROUND: Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m(2) intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m(2) on day 1 of cycle 1, and 500 mg/m(2) on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090. FINDINGS: Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7-20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3-13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150-0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0·203, 95% CI 0·150-0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. INTERPRETATION: In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. FUNDING: Janssen Research & Development.

1st Department of Propedeutic Medicine University of Athens Athens Greece

Center for CLL University of Pennsylvania Philadelphia PA USA

Department 1 of Internal Medicine and German CLL Study Group University of Cologne Cologne Germany

Department 1 of Internal Medicine Center of Integrated Oncology University of Cologne and Cologne Cluster of Excellence in Cellular Stress Responses in Aging Associated Diseases Cologne Germany

Department of Cancer Prevention Faculty of Public Health Silesian Medical University Katowice Poland

Department of Haematology Derriford Hospital Plymouth UK

Department of Hematology Cherkassy Regional Oncological Center Cherkassy Ukraine

Department of Hematology Fundaleu Buenos Aires Argentina

Department of Hematology Karolinska University Hospital Department of Oncology Pathology Karolinska Institutet Stockholm Sweden

Department of Internal Medicine Hematology and Oncology Masaryk University Hospital Brno Jihlavska Brno Czech Republic

Division of Hematology and Bone Marrow Transplantation Chaim Sheba Medical Center Tel Hashomer and Sackler School of Medicine University of Tel Aviv Tel Aviv Israel

Division of Hematology Dokuz Eylul University Izmir Turkey

Division of Medical Oncology British Columbia Cancer Agency Vancouver BC Canada

Hematology Department Hospital Universitario La Princesa IIS IP Madrid Spain

Hôpital Haut Lévêque Bordeaux Pessac France

IEP São Lucas Hemomed Oncologia e Hematologia São Paulo Brazil

Janssen Research and Development High Wycombe UK

Janssen Research and Development Raritan NJ USA

Janssen Research and Development Spring House PA USA

John Theurer Cancer Center at Hackensack University Medical Center Hackensack NJ USA

Juravinski Cancer Centre McMaster University Hamilton ON Canada

Mayo Clinic Cancer Center Jacksonville FL USA

Nizhny Novogorod Regional Clinical Hospital Nizhny Novogorod Russia

Regional Clinical Hospital Ryazan Russia

Universitaire Ziekenhuizen Leuven Leuven Belgium

Washington University School of Medicine Siteman Cancer Center St Louis MO USA

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